RARE DISEASE
Glanzmann thrombasthenia
Glanzmann thrombasthenia
Glanzmann thrombasthenia
Drug discovery
5
drugs
With orphan designations
Overview
Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet disorder caused by defective or deficient GPIIb/IIIa receptors, impairing fibrinogen-mediated platelet aggregation. Affected individuals present with mucocutaneous bleeding (epistaxis, gingival hemorrhage, menorrhagia) and prolonged bleeding post-trauma/surgery. Diagnosis requires platelet aggregation studies and flow cytometry confirming absent/reduced αIIbβ3 integrin expression [1][11][16].
Burden
Frequent bleeds: 50% experience ≥1 daily bleed (skin/mucosal), 13% report >500 annual episodes [4][9].
Psychosocial impact: 38% miss school/work, 33% report childhood bullying, and 21% face employer skepticism [7][14].
Women face heightened risks: 74% use hormonal contraceptives to suppress menstruation; 11% require emergency care for obstetric bleeding [4][14].
Therapies
Acute bleeding: Antifibrinolytics (tranexamic acid), recombinant factor VIIa (rFVIIa), and HLA-matched platelet transfusions (limited by antibody development in 20-30% of cases) [3][8][16].
Prophylaxis: rFVIIa or hormonal therapy (e.g., combined oral contraceptives) for recurrent menorrhagia [6][18].
Curative options: Hematopoietic stem cell transplantation (reserved for severe cases due to risks) [11].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
472 drug discovery papers about Glanzmann thrombasthenia, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
472 drug discovery papers about Glanzmann thrombasthenia, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-30 | Life-threatening gingival bleeding after scaling and root planning in a patient with Glanzmann Thrombasthenia despite recombinant Factor VIIa prophylaxis: the role of periodontal inflammation
Objective: Glanzmann thrombasthenia is a rare inherited platelet function disorder characterized by impaired platelet aggregation and mucocutaneous bleeding. Gingival bleeding is frequently observed in affected patients and is often attributed solely to the underlying hematologic disorder. However, local inflammatory factors may significantly influence bleeding severity. Case presentation: A patient with Glanzmann thrombasthenia presented with severe gingival inflammation and persistent gingival bleeding. Baseline periodontal examination revealed a plaque index of 1.9, a gingival index of 2.5, and bleeding on probing at 70% of sites. Prior to periodontal treatment, 6000 µg of recombinant factor VIIa was administered prophylactically. Treatment followed World Federation of Hemophilia recommendations. Non-surgical periodontal therapy including Scaling and Root Planing was performed. Despite administration of an additional 4000 µg factor VIIa post-procedure, severe gingival bleeding occurred. The patient’s hemoglobin level decreased from 9 g/dL to 3.3 g/dL and hospitalization was required for three days. During hospitalization the patient received 7 units of platelet and plasma transfusion and 6 units of packed red blood cells. After recovery and strict plaque control, periodontal parameters improved significantly, with plaque index decreasing to 0.4, gingival index to 0.5, and bleeding on probing to 8%. Conclusion: This case suggests that periodontal inflammation may exacerbate gingival bleeding in patients with Glanzmann thrombasthenia and may reduce the effectiveness of hemostatic therapy. Control of periodontal inflammation may therefore play an important role in the management of gingival bleeding in patients with platelet function disorders.
2026-04-01 | Acquired Platelet Dysfunction Secondary to Myelodysplastic Neoplasm: Successful Resolution With Neoplasm‐Directed Therapy
Acquired platelet dysfunction has been reported as a complication of hematologic malignancies. Diagnosis and management of platelet dysfunction with a concomitant myeloid disorder can be challenging, and there is a need for real‐world experience reports to help clinicians recognize these entities and manage them accordingly. Herein, we report a case of a 68‐year‐old female patient who was initially diagnosed with acquired platelet dysfunction disease (Glanzmann thrombasthenia [GT] versus alpha‐storage disease) and was found to have myelodysplastic neoplasm (MDS). By giving an MDS‐directed therapy (noncytotoxic dose hypomethylating agent [HMA] + venetoclax), the patient was able to achieve good disease control and a significant improvement of her platelet function disorder.
2026-03-04 | Glanzmann thrombasthenia presenting with upper gastrointestinal bleeding: a case series and review of the literature.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a defect in the platelet integrin αIIbβ3. While mucocutaneous bleeding is typical, gastrointestinal (GI) bleeding is not uncommon and can be a potentially severe complication. A total of six patients, including four female and two male individuals with type I GT, presented with massive upper GI bleeding of unknown cause. Treatment was selected based on the severity of each case and included a combination of recombinant activated factor VII (rFVIIa), tranexamic acid, endoscopic intervention, and supportive care. Genetic studies were performed for each patient. The endoscopic findings were heterogeneous, varying from normal mucosa to visible vessels, polyps, and arteriovenous malformations. All cases were managed successfully. The unpredictable nature of GI bleeding in patients with GT highlights the need for careful clinical assessment and a multidisciplinary management approach. Bleeding control was achieved through the use of antifibrinolytic agents and recombinant factor VIIa, which also reduces the risk of platelet alloimmunization. A possible link between certain ITGB3 variants and severe bleeding suggests phenotypic variability. This case series highlights the role of careful management strategies in reducing morbidity among patients with GT and adds to the limited literature on gastrointestinal bleeding in this population.
2026-01-27 | Pulmonary thromboembolism in Glanzmann Thrombasthenia: a case report and systematic literature review.
Glanzmann Thrombasthenia (GT) is a congenital platelet disorder characterized by a life-long bleeding tendency, historically considered protective against thrombosis. This report describes a rare case of pulmonary embolism (PE) in a patient with GT, challenging this assumption and highlighting a critical management paradox. A 55-year-old woman with GT underwent elective cervical discectomy. Her perioperative hemostatic regimen included a single prophylactic dose of recombinant Factor VIIa (90 µg/kg), platelet transfusions (preoperative and daily for 3 days), and tranexamic acid. Two months postoperatively, she presented with hemoptysis. CT pulmonary angiography confirmed bilateral segmental and subsegmental PE with pulmonary infarctions. Anticoagulation with apixaban was initiated, leading to symptom resolution and thrombus regression. Therapy was discontinued after four months following a spontaneous hemarthrosis, which was managed successfully. Provoked PE can occur in GT patients following major surgery and hemostatic support. Apixaban was effective for short-term treatment, but the subsequent bleeding complication highlights the narrow therapeutic window and the need to limit anticoagulation duration in this population.
2025-12-17 | International Practices in Managing Preconception, Pregnancy and Childbirth in Women With Glanzmann Thrombasthenia: A Survey From the European Association of Haemophilia and Allied Disorders (EAHAD).
Glanzmann thrombasthenia (GT) is an inherited platelet disorder resulting in severely reduced platelet aggregation and increased bleeding tendency. Pregnancy and childbirth in women with GT present significant challenges for both mother and child. The aim of this study was to present the current clinical practices in pregnancy and childbirth in GT. A survey on the management of the preconception phase, pregnancy and childbirth in women with GT was conducted by the European Association of Haemophilia and Allied Disorders. Thirty-seven responses from 18 countries were analysed. Almost all respondents recommended multidisciplinary preconception counselling, though 11% lack access to obstetrics and gynaecology services focused on bleeding disorders. Delay in conceiving was reported by 62%. Ninety-one percent of respondents indicated that they would screen for platelet alloimmunisation; however, the timing of screening varied. The recommended treatment to prevent postpartum haemorrhage (PPH) most often comprised tranexamic acid (TXA) and recombinant activated factor VII (rFVIIa) (25%) or TXA, rFVIIa and platelet transfusion (22%). The latter combination was also the most frequently recommended treatment to have on standby. Seventy-five percent would advise a mode of delivery as per obstetric indication and 69% would recommend to avoid neuraxial anaesthesia. Half of the respondents would add pharmacological thromboprophylaxis. There is general consensus on the importance of preconception counselling, the screening for platelet alloimmunisation and the preferred mode of delivery. Opinions regarding the treatment of PPH and the use of thromboprophylaxis vary. The next step is to improve guideline implementation in daily practice while working toward an international consensus-based guideline.
cell therapies
2025-11-24 | Perioperative Platelet Transfusion Strategies and Multidisciplinary Collaboration Experience in Glanzmann Thrombasthenia Caused by ITGA2B Gene Variation During Pregnancy: A Case Report.
To explore multidisciplinary peripartum management strategies and clinical implications for Glanzmann thrombasthenia (GT) caused by ITGA2B gene variation during pregnancy. A 33-year-old woman at 38+ 5weeks of gestation, diagnosed with GT, was confirmed with biallelic pathogenic ITGA2B mutations (chr17:42452041 and chr17:42,457,372). There was no history of consanguineous marriage in the past three generations of her family. Coagulation dysfunction was observed during pregnancy (fibrinogen: 2.69 g/L; thromboelastography (TEG) maximum clot strength: 12 mm). A multidisciplinary team (MDT) recommended preoperative transfusion of 3 therapeutic doses of platelets and 10 units of cryoprecipitate, with dynamic TEG monitoring showing improved clot strength (post-transfusion maximum clot strength: 29.2 mm). A cesarean section delivered a healthy male infant (3455 g, Apgar score 10). Intraoperative bleeding (900 mL) and postoperative incisional oozing were controlled with compression bandages and platelet transfusion. Both mother and infant had favorable outcomes, with the incision achieving Grade II/A healing. Individualized coagulation regulation, multidisciplinary collaboration, dynamic TEG-guided platelet transfusion, and comprehensive postoperative hemostatic management are critical for GT with pregnancy. This case provides practical insights into peripartum care for GT patients.
2024-10-01 | A Rare Bleeding Disorder: Glanzmann Thrombasthenia
Glanzmann Thrombasthenia (GT) is a rare and severe inherited bleeding disorder caused by dysfunction or absence of glycoprotein IIb-IIIa on the platelet membrane. Its occurrence rate is approximately 1 in 1.000.000 individuals, yet it tends to be more prevalent in communities with higher rates of consanguinity. The most common clinical presentations are unexplained mucocutaneous bleeding, purpura, epistaxis, gum bleeding and menorrhagia. During surgical procedures, a prolonged bleeding time and the absence of platelet aggregation on peripheral smears suggest Glanzmann Thrombasthenia. Two young women patients, sisters, referred to our Department of Oral and Maxillofacial Surgery for tooth extraction. Both sisters have the same bleeding disorder, Glanzmann thrombastenia (GT). After intraoral and radiological evaluation their treatment plans were formed which included dental extraction in both cases. The consultation with the hematology department resulted in the decision to proceed with platelet transfusion and the use of antifibrinolytic drugs. Extractions in both cases were done in atraumatic and careful approach and both healed uneventfully. Without any serious complications of bleeding. In patients with GT, early diagnosis and performing surgical procedures under appropriate precautions can help prevent bleeding complications. Surgical procedure can be safely performed with collaboration with a hematologist. Platelet transfusion is the standard treatment during the perioperative and postoperative periods for patients with GT. The management of our two cases indicates that proper application of a comprehensive transfusion protocol may prevent excessive postoperative bleeding. GT can be a severe bleeding disorder, however, an excellent prognosis can be achieved with careful supportive care.
2024-05-11 | Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations.
Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA-matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA-matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. We found 20 articles describing platelet transfusion policies in 483 GT-patients and 29 BSS-patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS-patients, including one child. Fifteen respondents gave preventive HLA-matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT-patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor-platelets in acute settings. Elective HLA-matching for GT and BSS-patients is already conducted by most Dutch (pediatric) hematologists. HPA-matching is mainly applied when HPA-antibodies are formed. Based on the current literature and the survey, recommendations are proposed.
2023-12-07 | Multidisciplinary management of a pregnancy complicated by Glanzmann thrombasthenia: A case report.
Glanzmann thrombasthenia (GT) is a rare, autosomal recessive disorder of platelet glycoprotein IIb-IIIa receptors. Pregnant patients with GT are at increased risk of maternal and fetal bleeding. There is a paucity of literature on the peripartum management of patients. We present the antepartum through the postpartum course of a patient with GT who was managed by a multidisciplinary approach that included communication across maternal-fetal medicine, hematology, transfusion medicine, and anesthesiology services. In addition to routine prepartum obstetric imaging and hematologic laboratory studies, we proactively monitored the patient for anti-platelet antibodies every 4-6 weeks to gauge the risk for neonatal alloimmune thrombocytopenia. Furthermore, we prioritized uterotonics, tranexamic acid, and transfusion of HLA-matched platelets to manage bleeding for mother and fetus intrapartum through the postpartum periods. To date, there are limited guidelines for managing bleeding or preventing alloimmunization during pregnancy in patients with GT. Here, we present a complex case with aggressive management of bleeding prophylactically for the mother while serially monitoring both mother and fetus for peripartum bleeding risks and events. Moreover, future studies warrant continued evaluation of these approaches to mitigate increased bleeding risks in subsequent pregnancies.
2022-12-15 | Stem Cell Transplantation in Glanzmann's Thrombasthenia: A Report of Two Adult Patients.
Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by mucocutaneous bleeding. At molecular level, defect in platelet receptor glycoprotein (GP) IIb/IIIa leads to defective platelet aggregation. Anti-fibrinolytic agents, platelet transfusions, and factor rVIIa are used for prophylaxis before invasive procedures and treatment of bleeding events. Allogeneic stem cell transplant is the only curative option. Here, we report cases of two adult male patients who underwent matched sibling donor stem cell transplantation for GT with recurrent bleeding requiring platelet and red cell transfusions. Both showed marked improvement in quality of life. To conclude, stem cell transplant is a viable treatment option for severe, difficult-to-control cases of GT. Key Words: Platelet disorders, Hematopoietic stem cell transplantation, Thrombasthenia.
proteins
2026-07-11 | Efficacy and safety of recombinant activated factor VII for secondary prophylaxis in patients with Glanzmann thrombasthenia.
Glanzmann thrombasthenia (GT) is a rare inherited platelet disorder associated with recurrent and sometimes life-threatening bleeding. Recombinant activated factor VII (rFVIIa) is approved for treatment of bleeding episodes or surgical prophylaxis in patients with GT who are refractory or alloimmunized to platelet transfusions. However, evidence for its use as secondary prophylaxis remains scarce. This study described the efficacy and safety of rFVIIa secondary prophylaxis in patients with GT and recurrent and uncontrolled bleeding despite standard therapy. A multicenter, retrospective study of patients with GT included in the Spanish Registry of Patients with Inherited Platelet Disorders (RETPLAC) was performed. We evaluated bleeding severity using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) and calculated the annualized bleeding rate (ABR) before and during rFVIIa prophylaxis. Of the 37 patients with GT included in RETPLAC, 4 patients received regular rFVIIa prophylaxis due to recurrent severe bleeding. Median baseline ISTH-BAT score was 13.5 (IQR, 9.5-18), and median preprophylaxis ABR was 3 (IQR, 3-5.25). All patients received rFVIIa of 90 μg/kg, 3 twice weekly and 1 monthly. The median prophylaxis duration was 7.5 months (IQR, 6.75-12). Prophylaxis led to a 57.1% overall reduction in ABR, with resolution of severe bleeding in 2 patients and reduction in frequency in the remaining 2. Three patients achieved transfusion independence. All patients showed improvement in hemoglobin and iron profile. No thrombotic or adverse events occurred. Secondary prophylaxis with rFVIIa may be an effective option in patients with GT and recurrent severe bleeding unresponsive to standard therapy. Prospective studies are necessary to optimize dosing schedules and define its role in secondary prophylaxis.
2026-07-09 | [Current diagnosis and treatment of congenital platelet function disorders: focus on Glanzmann thrombasthenia and Bernard-Soulier syndrome].
Platelet function is regulated by numerous molecules, and congenital abnormalities of these molecules result in a variety of congenital platelet function disorders. Among these, Glanzmann thrombasthenia (GT), caused by a congenital deficiency or molecular abnormality in GPIIb-IIIa (αIIbβ3), and Bernard-Soulier syndrome (BSS), caused by a congenital deficiency or molecular abnormality in the GPIb-IX-V complex, are representative disorders that manifest as severe bleeding tendency from infancy. GT and BSS are diagnosed mainly by flow cytometry of membrane glycoproteins in addition to conventional light transmission aggregometry. Platelet transfusions are indicated for bleeding refractory to standard hemostatic measures, and recombinant factor VIIa (rFVIIa) has been shown to be effective in GT. rFVIIa has conventionally been used in GT patients refractory to platelet transfusion due to alloantibody production, but is now available in Japan regardless of alloantibody status or platelet transfusion refractoriness. rFVIIa should be considered especially in patients at risk of alloantibody production due to platelet transfusion.
2026-05-01 | Multidisciplinary approaches to coexisting Glanzmann thrombasthenia and juvenile polyposis syndrome.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder from defects in the αIIbβ3 integrin receptor, impairing platelet aggregation and often overlooked due to normal platelet counts. Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder with multiple gastrointestinal polyps and increased colorectal cancer risk. Their co-occurrence is exceedingly rare and challenging. We report a 19-year-old male who was diagnosed with GT at age 5 after rectal bleeding from a gastrointestinal polyp requiring polypectomy and transfusions; platelet aggregation studies confirmed GT. At age 9, genetic testing established JPS. In 2014 he developed recurrent severe bleeding-hematochezia, melena, and hemarthrosis-managed with recombinant activated factor VII (rFVIIa), blood transfusions, and supportive care including vitamin D. Additional findings included duodenal lymphangioma requiring resection, vitamin D deficiency with bone pain and complex regional pain syndrome, and chronic idiopathic hypertension treated with antihypertensives. This case highlights rFVIIa effectiveness and the need for multidisciplinary, long-term follow-up and care.
2026-04-09 | Platelet transfusion refractoriness in Glanzmann thrombasthenia: a case report with literature review.
Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder characterized by a deficiency or dysfunction of the αIIbβ3 integrin, leading to impaired platelet aggregation. Platelet transfusion refractoriness (PTR) represents a therapeutic challenge, often resulting from alloimmunization against HLA antigens or the αIIbβ3 complex. We report the case of a patient with type I GT, who presented with recurrent mucosal hemorrhages and chronic anemia requiring repeated transfusions. By the age of 8 years, the patient developed transfusion refractoriness, with hemorrhagic episodes unresponsive to platelet transfusions. Immunologic investigations revealed anti-HLA and anti-αIIbβ3 antibodies. At 14 years of age, a severe hemorrhagic episode with rapid hemoglobin decline was successfully managed with recombinant activated factor VII (rFVIIa). Management of PTR in GT represents a major clinical challenge, frequently associated with anti-HLA or anti-αIIbβ3 antibodies. In high-resource settings, transfusion strategies are guided by antibody specificity: HLA-compatible or human platelet antigen-compatible platelets are used for patients with anti-HLA or anti-human platelet antigen antibodies, respectively, while rFVIIa is reserved for individuals with anti-αIIbβ3 antibodies. In LMIC such as Tunisia, prevention of alloimmunization through systematic leukoreduction is essential. When PTR occurs, donor selection by crossmatching, when feasible, and judicious use of rFVIIa for life-threatening hemorrhage remain key therapeutic options.
2026-04-08 | Congenital thrombopathies in southern Tunisia : A multicenter study.
congenital thrombopathies (CTs) are rare bleeding disorders resulting from platelet dysfunction which may also be associated with thrombocytopenia. To date, the prevalence of CT in Tunisia has not been established. The aim of this study was to describe the various types of CT and the associated hemorrhagic manifestations observed in a cohort from southern Tunisia. We retrospectively collected clinical and laboratory data of patients with CT who were followed up over 43 years (1982 - 2024) in the pediatric and hematology departements of a university hospital center in southern Tunisia. The diagnosis of thrombopathy was established based on flow cytometry analysis and/or light transmission aggregometry and/or molecular analysis. We identified 60 patients (35 men and 25 women). The mean age at diagnosis was 61.7 months (1 month-70 years). Consanguinity was noted in 71.6% of cases (n=43). A family history of thrombopathy was reported in 51.6% of cases (n=31). The presenting symptoms at diagnosis were spontaneous or provoked bleeding (n=56) and easy bruising associated with thrombocytopenia within the first 48 hours of life (n=1). The etiologies of the thrombopathies were as follows : Glanzmann thrombasthenia (n=54), Bernard Soulier syndrome (n=5) and Wiskott Aldrich syndrome (n=1). Glanzmann thrombasthenia was the most prevalent thrombopathy in our cohort, likely attributed to the high rate of consanguinity in our region.
antibodies
2026-02-01 | Antiboby mediated Acquired Glanzmann Thrombasthenia – a diagnostic and therapeutic challenge – with Concizumab as Promising Therapeutic Approach: A Case Report
Introduction Acquired Glanzmann thrombasthenia (aGT) is a rare autoimmune bleeding disorder caused by inhibitory antibodies against GPIIb/IIIa, leading to impaired platelet aggregation and severe bleeding. This closely mimics classic GT where isoantibodies render donor platelets ineffective. Thus, rFVIIa and antifibrinolytics are the treatment of choice [ 1 ]. Immunosuppressive approaches such as corticosteroids, intravenous immunoglobulins, and rituximab show variable efficacy, particularly in the presence of IgM antibodies [ 2 ] [ 3 ]. A 12‑year‑old boy, ten years after heart transplantation due to CMV‑induced myocarditis, presented with recurrent severe gastrointestinal bleeding and extensive petechiae. Routine coagulation parameters were normal, except mild thrombocytopenia (around 100,000/µl). After diagnostic gastrointestinal biopsies, he suffered life-threatening hemorrhage requiring massive transfusion of erythrocytes, platelets, fresh frozen plasma, rFVIIa, fibrinogen, and FXIII to stabilize. Method Light transmission aggregometry (LTA) showed absent aggregation responses except ristocetin (1M) consistent with the pattern of GT. MAIPA revealed platelet antibodies against the GPIIb/IIIa complex. LTA with platelets of a healthy control and patient`’s plasma failed to improve aggregation consistent with the hypothesis of antibody-mediated aGT. Further investigations with antibody depletion and purification raised the suspicion that besides IgG antibodies also IgM anti-platelet antibodies play a significant role in this thrombocytopathy. Next‑generation sequencing revealed a heterozygous LRBA deficiency as a potential cause of immune dysregulation. Results Specific treatment included plasma exchange, high‑dose corticosteroids, intravenous immunoglobulins, rituximab, daratumumab, and abatacept, without improvement in platelet function. The patient experienced several life-threatening bleeding events, with only short term bleeding control upon administration of recombinant FVIIa and antifibrinolytics, followed by severe rebleeding with every dose reduction. Due to the need for prophylactic measures to prevent refractory bleedings, Concizumab, a monoclonal antibody inhibiting tissue factor pathway inhibitor (TFPI), was initiated as off‑label therapy after approval for cost coverage. Following subcutaneous administration, bleeding episodes ceased for the first time since disease onset. No further major hemorrhages occurred, petechiae regressed, and transfusion requirements stopped. Conclusion Acquired GT can cause sudden life-threatening bleedings even in children. This case demonstrates that aGT with persistent IgM anti‑GPIIb/IIIa antibodies can be resistant to standard treatments and immunosuppression. Concizumab led to sustained clinical improvement and effective bleeding control , representing a promising therapeutic approach for refractory aGT. TFPI inhibition may offer a novel concept for managing severe autoimmune and congenital platelet function disorders. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-01 | Procoagulant Platelets and Thrombin Generation in Glanzmann Thrombasthenia: Insights into Bleeding and the Failing Compensatory Mechanism with Desmopressin on Platelets
Introduction Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet disorder caused by mutations in the ITGA2B or ITGB3 genes, leading to defective integrin αIIbβ3 function and impaired platelet aggregation. GT patients exhibit severe bleeding symptoms, but the relationship between procoagulant platelets, thrombin generation, and bleeding severity remains poorly understood. Studies in hemophilia suggest a compensatory role for procoagulant platelets in mitigating bleeding severity, as highlighted by recent findings [ 1 ]. However, the procoagulant potential of platelets has not been explored in GT patients, where integrin αIIbβ3 dysfunction fundamentally alters platelet behavior. Objective: This study aims to evaluate the procoagulant potential of platelets and their impact on thrombin generation in GT patients, providing insights into compensatory mechanisms in hemostasis. Method A total of 9 samples from 5 Glanzmann patients and 9 healthy controls, were analyzed. Platelets were quantified using flow cytometry, thrombin generation was assessed via calibrated automated thrombography, and bleeding severity was evaluated using the ISTH-BAT (scores: 17–45). The impact of Desmopressin on platelet procoagulant activity was also investigated. Results The procoagulant platelet formation was significantly reduced in GT patients (8.87%, n =9) compared to healthy controls (34.46%, n =24, p =0.0002) after TRAP-6/CVX stimulation. Surprisingly, despite this reduction, GT patients demonstrated significantly increased thrombin generation (area under the curve: 2278 nM·min vs. 1541 nM·min in controls, p =0.0021). The thrombin peak was not significantly different ( p =0.0671; 126.8 nM vs. 96.37 nM); however, the lag time ( p =0.0008; 12.35 vs. 7.286 min) and time to peak ( p =0.0019; 25.45 vs. 17.75 min) were markedly prolonged in GT patients. Notably, the ISTH-BAT scores did not correlate with procoagulant platelet levels, suggesting that bleeding severity is independent of procoagulant potential induced by TRAP-6/CVX. Desmopressin significantly enhanced procoagulant platelet formation in healthy controls ( p =0.0095; 28.73% vs. 12.15%) but showed no effect in GT patients ( p =0.4983; 6.037% vs. 4.904%). Conclusion GT patients exhibit a profound reduction in procoagulant platelet formation but demonstrate compensatory increases in thrombin generation, albeit with delayed kinetics. This compensatory mechanism does not translate into reduced bleeding severity, as evidenced by the lack of correlation with ISTH-BAT scores. The inability of Desmopressin to enhance procoagulant platelet formation in GT further underscores the unique pathophysiology of the disorder. Future studies are needed to explore therapeutic strategies targeting thrombin generation pathways to mitigate bleeding in GT patients. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-03 | Sutacimig, a novel bispecific antibody for prophylactic treatment of glanzmann thrombasthenia: Analysis of a Phase 2 study
Abstract Background: Sutacimig is a bispecific antibody designed to bind and accumulate endogenous factor VIIa (FVIIa) and localize it to activated platelets via TLT-1, thereby enhancing thrombin generation at sites of vascular injury. Glanzmann thrombasthenia (GT) is a severe genetic bleeding disorder characterized by deficient or dysfunctional expression of αIIbβ3 integrin, resulting in impaired platelet aggregation and frequent bleeding episodes. No prophylactic therapy exists, leading to substantial morbidity including iron deficiency anemia, heavy menstrual bleeding, and impaired quality of life. Early results from this study evaluating sutacimig as prophylactic therapy for GT demonstrated encouraging safety and >50% reduction in the median annualized treated bleeding rate (ATBR) (Sivapalaratnam, EAHAD & ISTH, 2025). Here, we present interim results from the fully enrolled Phase 2 study (NCT06211634); complete results will be presented at ASH. Methods: We conducted a multicenter, open-label study evaluating prophylactic subcutaneous sutacimig in adults (18-67 years) with confirmed GT. Following completion of the single ascending dose module the multiple ascending dose (MAD) module opened. Treated bleeding events were prospectively recorded in a 6-week run-in period; subsequently, participants received sutacimig for 12 weeks with option to continue in a long-term extension. The primary endpoint in the MAD was safety, with additional endpoints including pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy based on ATBR reduction. Results: As of data cutoff on May 23, 2025, the MAD was fully enrolled with n=34 participants; median age 40.5 years, 47% female. Participants were enrolled into four dosing regimens: 0.3 mg/kg Q2W (n=11); 0.6 mg/kg Q2W (n=13); 0.9 mg/kg Q2W (n=5); 0.3 mg/kg Q1W (n=5). Median exposure in the MAD plus long-term extension was 3.2 months (range 1.7-11.3). AEs were reported in 82% of participants with the majority of AEs graded as mild to moderate. The most common reported AEs (≥10%) were headache (18%), nasopharyngitis (18%), D-dimer elevation (18%), dizziness (12%), and fatigue (12%). Neutralizing anti-drug antibodies developed in 4/34 participants; 2/4 resolved with continued dosing without clinical sequelae. A DVT (Grade 2) was observed in one participant in the 0.9 mg/kg Q2W cohort who discontinued due to this AE. Dosing in this cohort was subsequently suspended. The event is resolving with outpatient treatment. PK and PD (FVIIa) demonstrated a dose-proportional increase with FVIIa accumulation of ~2-4 fold above baseline at ongoing dose levels (0.3-0.6 mg/kg). Interim efficacy analyses demonstrated sutacimig achieved >50% reduction in median ATBR compared to run-in period. Conclusions: In this interim analysis, sutacimig was well tolerated at ongoing dose levels (0.3-0.6 mg/kg) with evidence of clinical activity, with a >50% reduction in median ATBR with sutacimig prophylaxis. Updated safety and efficacy analyses will be conducted following completion of 12-week follow-up for all participants. These data are expected to inform dose selection and support planning for a Phase 3 trial evaluating prophylactic sutacimig for GT.
2025-04-16 | Advanced diagnostics and novel therapeutics for platelet function disorders
Platelet function plays a critical role in hemostasis, and dysfunction in this mechanism is implicated in a range of bleeding disorders. The most rare inherited platelet function disorders (IPFDs) are relatively easy to diagnose. However, the more prevalent IPFDs often show a high diagnostic difficulty, leading to underdiagnosis. In terms of treatment of IPFD patients, no prophylactic treatment is available, causing high patient burden and relatively low quality of life for patients suffering from a severe IPFD. This thesis describes novel diagnostic and therapeutic approaches for this group of disorders. Advanced diagnostics … In Chapter 2, we described the characterization of a tetrameric nanobody-based glycoprotein VI (GPVI) platelet agonist and compared it to current agonists used in platelet diagnostics, that are hard to standardize and difficult to produce. We showed that our nanobody is able to discriminate between healthy controls and GPVI-related platelet disorders to a similar extent as collagen or cross-linked collagen-related peptide (CRP-XL). In this way, we provide a more stable, easier to produce alternative to current GPVI agonists, which is beneficial for standardization of platelet diagnostics. In Chapter 3, we have validated a novel whole blood-based rapid test for delta storage pool disease (δ-SPD), based on platelet ATP secretion. The current standard for diagnosis of δ-SPD is laborious, has a long turn-around time and requires large volumes of blood. We aimed to introduce a microarray that decreases the labor intensiveness, turn-around time and required volume of blood. With its high sensitivity, this test is able to exclude δ-SPD, decreasing the need to send all patients for more advanced diagnostic techniques. In Chapter 4, we have compared the platelet proteome of healthy controls and people with Glanzmann thrombasthenia (GT). We have shown that platelets from GT patients show downregulation of several platelet specific α-granule proteins. … and novel therapeutics for inherited platelet function disorders In Chapter 5, we introduced a potential novel prophylactic treatment for inherited bleeding disorders. HMB-001 is a bispecific antibody that recognizes (activated) coagulation factor VII (FVII(a)) and TREM-like transcript-1 (TLT-1) on the activated platelet surface, thereby targeting FVIIa to the platelet surface and boosting fibrin formation to compensate for defects in primary hemostasis. Our preclinical data has shown that HMB-001 is effective in enhancing fibrin formation ex vivo, prolonging endogenous FVIIa half-life in nonhuman primates and potentiating FVIIa hemostatic activity in mouse bleeding studies. HMB-001 has therefore potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
2024-08-22 | Targeting tissue factor pathway inhibitor with concizumab to improve hemostasis in patients with Glanzmann thrombasthenia: an in vitro study.
Glanzmann thrombasthenia (GT) is caused by an inherited defect of platelet αIIbβ3 integrin. Concizumab, a monoclonal antibody specific for tissue factor pathway inhibitor, abolishes its anticoagulant effect. To evaluate the in vitro ability of concizumab to improve hemostasis in GT. The effects of concizumab were evaluated in whole blood or platelet-rich plasma from GT patients (n = 5-9) using a thrombin generation assay, rotational thromboelastometry (ROTEM), a global fibrinolytic capacity assay, and a flow chamber assay (Total Thrombus formation Analysis System). Washed platelets (WPs) and 20 nM recombinant activated factor VII (rFVIIa) were included for comparison. The lag time in the thrombin generation assay was significantly longer (+85%; P < .0001) in GT patients than in controls. WPs, rFVIIa, and concizumab each significantly improved thrombin generation profiles. The ROTEM clotting time (CT) was significantly longer in GT patients than in controls (677 seconds vs 523 seconds; P = .03). However, CT improved after adding WPs, rFVIIa, or concizumab. Under flow, occlusive thrombi were present in all healthy controls after 10 minutes, whereas platelet-fibrin depositions were not seen in GT patients. Subocclusive or occlusive thrombi formed when GT blood was mixed with WPs, rFVIIa, or concizumab. Clots in GT platelet-rich plasma were more susceptible to fibrinolysis and were improved by WPs, rFVIIa, or concizumab. Concizumab enhanced thrombin generation, decreased the ROTEM CT, improved thrombus formation under flow, and reduced clot lysis. Our results demonstrate the potential of concizumab for subcutaneous prophylaxis in GT patients.
other
2026-05-29 | Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.
Glanzmann Thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. While GT patients typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 GT patients, eight consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized megakaryocyte cell lines (imMKCLs), focusing on two modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3D silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production, independent of the type of variant. While TRAP-activated in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 prior to activation mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3 deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, while re-expression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.
2025-11-27 | Molecular Pathogenesis of Inherited Platelet Dysfunction.
Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann's thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the αIIbβ3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y12, and thromboxane A2[TxA2]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA2 pathway enzymes), and granule biogenesis disorders such as Hermansky-Pudlak and Chediak-Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype-phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis.
2020-07-14 | Integrin β3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion.
Integrin β3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether β3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with β3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an αIIb deficiency or healthy subjects. The β3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that β3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine)720-722 motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/β3/LPL complex that is required for β3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in β3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH720-722-mutated β3 genes. This study reveals a hypertriglyceridemia in both β3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of β3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with β3-deficient Glanzmann thrombasthenia.
2016-01-20 | Megakaryocyte- and megakaryocyte precursor–related gene therapies
Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual's lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.
2015-07-01 | Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options
Abstract: Glanzmann’s thrombasthenia (GT) is a genetic platelet surface receptor disorder of GPIIb/IIIa (ITG αIIbß3), either qualitative or quantitative, which results in faulty platelet aggregation and diminished clot retraction. Spontaneous mucocutaneous bleeding is common and can lead to fatal bleeding episodes. Control and prevention of bleeding among patients with GT is imperative, and remains challenging. Local measures, including anti-fibrinolytic therapy, with or without platelet transfusions, used to be the mainstay of therapy. However, in recent years the use of recombinant factor VIIa (rFVIIa) has increased significantly, with excellent response rates in treating and preventing hemorrhage among GT patients. Gene therapy and stem cell transplantation offer a potential cure of this disease, but both are costly and remain experimental at this point. This manuscript offers a comprehensive review of our understanding of GT and the available treatment options. Keywords: Glanzmann, thrombasthenia, treatment
small molecules
2026-07-30 | Life-threatening gingival bleeding after scaling and root planning in a patient with Glanzmann Thrombasthenia despite recombinant Factor VIIa prophylaxis: the role of periodontal inflammation
Objective: Glanzmann thrombasthenia is a rare inherited platelet function disorder characterized by impaired platelet aggregation and mucocutaneous bleeding. Gingival bleeding is frequently observed in affected patients and is often attributed solely to the underlying hematologic disorder. However, local inflammatory factors may significantly influence bleeding severity. Case presentation: A patient with Glanzmann thrombasthenia presented with severe gingival inflammation and persistent gingival bleeding. Baseline periodontal examination revealed a plaque index of 1.9, a gingival index of 2.5, and bleeding on probing at 70% of sites. Prior to periodontal treatment, 6000 µg of recombinant factor VIIa was administered prophylactically. Treatment followed World Federation of Hemophilia recommendations. Non-surgical periodontal therapy including Scaling and Root Planing was performed. Despite administration of an additional 4000 µg factor VIIa post-procedure, severe gingival bleeding occurred. The patient’s hemoglobin level decreased from 9 g/dL to 3.3 g/dL and hospitalization was required for three days. During hospitalization the patient received 7 units of platelet and plasma transfusion and 6 units of packed red blood cells. After recovery and strict plaque control, periodontal parameters improved significantly, with plaque index decreasing to 0.4, gingival index to 0.5, and bleeding on probing to 8%. Conclusion: This case suggests that periodontal inflammation may exacerbate gingival bleeding in patients with Glanzmann thrombasthenia and may reduce the effectiveness of hemostatic therapy. Control of periodontal inflammation may therefore play an important role in the management of gingival bleeding in patients with platelet function disorders.
2026-04-01 | Acquired Platelet Dysfunction Secondary to Myelodysplastic Neoplasm: Successful Resolution With Neoplasm‐Directed Therapy
Acquired platelet dysfunction has been reported as a complication of hematologic malignancies. Diagnosis and management of platelet dysfunction with a concomitant myeloid disorder can be challenging, and there is a need for real‐world experience reports to help clinicians recognize these entities and manage them accordingly. Herein, we report a case of a 68‐year‐old female patient who was initially diagnosed with acquired platelet dysfunction disease (Glanzmann thrombasthenia [GT] versus alpha‐storage disease) and was found to have myelodysplastic neoplasm (MDS). By giving an MDS‐directed therapy (noncytotoxic dose hypomethylating agent [HMA] + venetoclax), the patient was able to achieve good disease control and a significant improvement of her platelet function disorder.
2026-03-04 | Glanzmann thrombasthenia presenting with upper gastrointestinal bleeding: a case series and review of the literature.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a defect in the platelet integrin αIIbβ3. While mucocutaneous bleeding is typical, gastrointestinal (GI) bleeding is not uncommon and can be a potentially severe complication. A total of six patients, including four female and two male individuals with type I GT, presented with massive upper GI bleeding of unknown cause. Treatment was selected based on the severity of each case and included a combination of recombinant activated factor VII (rFVIIa), tranexamic acid, endoscopic intervention, and supportive care. Genetic studies were performed for each patient. The endoscopic findings were heterogeneous, varying from normal mucosa to visible vessels, polyps, and arteriovenous malformations. All cases were managed successfully. The unpredictable nature of GI bleeding in patients with GT highlights the need for careful clinical assessment and a multidisciplinary management approach. Bleeding control was achieved through the use of antifibrinolytic agents and recombinant factor VIIa, which also reduces the risk of platelet alloimmunization. A possible link between certain ITGB3 variants and severe bleeding suggests phenotypic variability. This case series highlights the role of careful management strategies in reducing morbidity among patients with GT and adds to the limited literature on gastrointestinal bleeding in this population.
2026-01-27 | Pulmonary thromboembolism in Glanzmann Thrombasthenia: a case report and systematic literature review.
Glanzmann Thrombasthenia (GT) is a congenital platelet disorder characterized by a life-long bleeding tendency, historically considered protective against thrombosis. This report describes a rare case of pulmonary embolism (PE) in a patient with GT, challenging this assumption and highlighting a critical management paradox. A 55-year-old woman with GT underwent elective cervical discectomy. Her perioperative hemostatic regimen included a single prophylactic dose of recombinant Factor VIIa (90 µg/kg), platelet transfusions (preoperative and daily for 3 days), and tranexamic acid. Two months postoperatively, she presented with hemoptysis. CT pulmonary angiography confirmed bilateral segmental and subsegmental PE with pulmonary infarctions. Anticoagulation with apixaban was initiated, leading to symptom resolution and thrombus regression. Therapy was discontinued after four months following a spontaneous hemarthrosis, which was managed successfully. Provoked PE can occur in GT patients following major surgery and hemostatic support. Apixaban was effective for short-term treatment, but the subsequent bleeding complication highlights the narrow therapeutic window and the need to limit anticoagulation duration in this population.
2025-12-17 | International Practices in Managing Preconception, Pregnancy and Childbirth in Women With Glanzmann Thrombasthenia: A Survey From the European Association of Haemophilia and Allied Disorders (EAHAD).
Glanzmann thrombasthenia (GT) is an inherited platelet disorder resulting in severely reduced platelet aggregation and increased bleeding tendency. Pregnancy and childbirth in women with GT present significant challenges for both mother and child. The aim of this study was to present the current clinical practices in pregnancy and childbirth in GT. A survey on the management of the preconception phase, pregnancy and childbirth in women with GT was conducted by the European Association of Haemophilia and Allied Disorders. Thirty-seven responses from 18 countries were analysed. Almost all respondents recommended multidisciplinary preconception counselling, though 11% lack access to obstetrics and gynaecology services focused on bleeding disorders. Delay in conceiving was reported by 62%. Ninety-one percent of respondents indicated that they would screen for platelet alloimmunisation; however, the timing of screening varied. The recommended treatment to prevent postpartum haemorrhage (PPH) most often comprised tranexamic acid (TXA) and recombinant activated factor VII (rFVIIa) (25%) or TXA, rFVIIa and platelet transfusion (22%). The latter combination was also the most frequently recommended treatment to have on standby. Seventy-five percent would advise a mode of delivery as per obstetric indication and 69% would recommend to avoid neuraxial anaesthesia. Half of the respondents would add pharmacological thromboprophylaxis. There is general consensus on the importance of preconception counselling, the screening for platelet alloimmunisation and the preferred mode of delivery. Opinions regarding the treatment of PPH and the use of thromboprophylaxis vary. The next step is to improve guideline implementation in daily practice while working toward an international consensus-based guideline.
cell therapies
2025-11-24 | Perioperative Platelet Transfusion Strategies and Multidisciplinary Collaboration Experience in Glanzmann Thrombasthenia Caused by ITGA2B Gene Variation During Pregnancy: A Case Report.
To explore multidisciplinary peripartum management strategies and clinical implications for Glanzmann thrombasthenia (GT) caused by ITGA2B gene variation during pregnancy. A 33-year-old woman at 38+ 5weeks of gestation, diagnosed with GT, was confirmed with biallelic pathogenic ITGA2B mutations (chr17:42452041 and chr17:42,457,372). There was no history of consanguineous marriage in the past three generations of her family. Coagulation dysfunction was observed during pregnancy (fibrinogen: 2.69 g/L; thromboelastography (TEG) maximum clot strength: 12 mm). A multidisciplinary team (MDT) recommended preoperative transfusion of 3 therapeutic doses of platelets and 10 units of cryoprecipitate, with dynamic TEG monitoring showing improved clot strength (post-transfusion maximum clot strength: 29.2 mm). A cesarean section delivered a healthy male infant (3455 g, Apgar score 10). Intraoperative bleeding (900 mL) and postoperative incisional oozing were controlled with compression bandages and platelet transfusion. Both mother and infant had favorable outcomes, with the incision achieving Grade II/A healing. Individualized coagulation regulation, multidisciplinary collaboration, dynamic TEG-guided platelet transfusion, and comprehensive postoperative hemostatic management are critical for GT with pregnancy. This case provides practical insights into peripartum care for GT patients.
2024-10-01 | A Rare Bleeding Disorder: Glanzmann Thrombasthenia
Glanzmann Thrombasthenia (GT) is a rare and severe inherited bleeding disorder caused by dysfunction or absence of glycoprotein IIb-IIIa on the platelet membrane. Its occurrence rate is approximately 1 in 1.000.000 individuals, yet it tends to be more prevalent in communities with higher rates of consanguinity. The most common clinical presentations are unexplained mucocutaneous bleeding, purpura, epistaxis, gum bleeding and menorrhagia. During surgical procedures, a prolonged bleeding time and the absence of platelet aggregation on peripheral smears suggest Glanzmann Thrombasthenia. Two young women patients, sisters, referred to our Department of Oral and Maxillofacial Surgery for tooth extraction. Both sisters have the same bleeding disorder, Glanzmann thrombastenia (GT). After intraoral and radiological evaluation their treatment plans were formed which included dental extraction in both cases. The consultation with the hematology department resulted in the decision to proceed with platelet transfusion and the use of antifibrinolytic drugs. Extractions in both cases were done in atraumatic and careful approach and both healed uneventfully. Without any serious complications of bleeding. In patients with GT, early diagnosis and performing surgical procedures under appropriate precautions can help prevent bleeding complications. Surgical procedure can be safely performed with collaboration with a hematologist. Platelet transfusion is the standard treatment during the perioperative and postoperative periods for patients with GT. The management of our two cases indicates that proper application of a comprehensive transfusion protocol may prevent excessive postoperative bleeding. GT can be a severe bleeding disorder, however, an excellent prognosis can be achieved with careful supportive care.
2024-05-11 | Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations.
Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA-matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA-matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. We found 20 articles describing platelet transfusion policies in 483 GT-patients and 29 BSS-patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS-patients, including one child. Fifteen respondents gave preventive HLA-matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT-patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor-platelets in acute settings. Elective HLA-matching for GT and BSS-patients is already conducted by most Dutch (pediatric) hematologists. HPA-matching is mainly applied when HPA-antibodies are formed. Based on the current literature and the survey, recommendations are proposed.
2023-12-07 | Multidisciplinary management of a pregnancy complicated by Glanzmann thrombasthenia: A case report.
Glanzmann thrombasthenia (GT) is a rare, autosomal recessive disorder of platelet glycoprotein IIb-IIIa receptors. Pregnant patients with GT are at increased risk of maternal and fetal bleeding. There is a paucity of literature on the peripartum management of patients. We present the antepartum through the postpartum course of a patient with GT who was managed by a multidisciplinary approach that included communication across maternal-fetal medicine, hematology, transfusion medicine, and anesthesiology services. In addition to routine prepartum obstetric imaging and hematologic laboratory studies, we proactively monitored the patient for anti-platelet antibodies every 4-6 weeks to gauge the risk for neonatal alloimmune thrombocytopenia. Furthermore, we prioritized uterotonics, tranexamic acid, and transfusion of HLA-matched platelets to manage bleeding for mother and fetus intrapartum through the postpartum periods. To date, there are limited guidelines for managing bleeding or preventing alloimmunization during pregnancy in patients with GT. Here, we present a complex case with aggressive management of bleeding prophylactically for the mother while serially monitoring both mother and fetus for peripartum bleeding risks and events. Moreover, future studies warrant continued evaluation of these approaches to mitigate increased bleeding risks in subsequent pregnancies.
2022-12-15 | Stem Cell Transplantation in Glanzmann's Thrombasthenia: A Report of Two Adult Patients.
Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by mucocutaneous bleeding. At molecular level, defect in platelet receptor glycoprotein (GP) IIb/IIIa leads to defective platelet aggregation. Anti-fibrinolytic agents, platelet transfusions, and factor rVIIa are used for prophylaxis before invasive procedures and treatment of bleeding events. Allogeneic stem cell transplant is the only curative option. Here, we report cases of two adult male patients who underwent matched sibling donor stem cell transplantation for GT with recurrent bleeding requiring platelet and red cell transfusions. Both showed marked improvement in quality of life. To conclude, stem cell transplant is a viable treatment option for severe, difficult-to-control cases of GT. Key Words: Platelet disorders, Hematopoietic stem cell transplantation, Thrombasthenia.
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2026-07-11 | Efficacy and safety of recombinant activated factor VII for secondary prophylaxis in patients with Glanzmann thrombasthenia.
Glanzmann thrombasthenia (GT) is a rare inherited platelet disorder associated with recurrent and sometimes life-threatening bleeding. Recombinant activated factor VII (rFVIIa) is approved for treatment of bleeding episodes or surgical prophylaxis in patients with GT who are refractory or alloimmunized to platelet transfusions. However, evidence for its use as secondary prophylaxis remains scarce. This study described the efficacy and safety of rFVIIa secondary prophylaxis in patients with GT and recurrent and uncontrolled bleeding despite standard therapy. A multicenter, retrospective study of patients with GT included in the Spanish Registry of Patients with Inherited Platelet Disorders (RETPLAC) was performed. We evaluated bleeding severity using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT) and calculated the annualized bleeding rate (ABR) before and during rFVIIa prophylaxis. Of the 37 patients with GT included in RETPLAC, 4 patients received regular rFVIIa prophylaxis due to recurrent severe bleeding. Median baseline ISTH-BAT score was 13.5 (IQR, 9.5-18), and median preprophylaxis ABR was 3 (IQR, 3-5.25). All patients received rFVIIa of 90 μg/kg, 3 twice weekly and 1 monthly. The median prophylaxis duration was 7.5 months (IQR, 6.75-12). Prophylaxis led to a 57.1% overall reduction in ABR, with resolution of severe bleeding in 2 patients and reduction in frequency in the remaining 2. Three patients achieved transfusion independence. All patients showed improvement in hemoglobin and iron profile. No thrombotic or adverse events occurred. Secondary prophylaxis with rFVIIa may be an effective option in patients with GT and recurrent severe bleeding unresponsive to standard therapy. Prospective studies are necessary to optimize dosing schedules and define its role in secondary prophylaxis.
2026-07-09 | [Current diagnosis and treatment of congenital platelet function disorders: focus on Glanzmann thrombasthenia and Bernard-Soulier syndrome].
Platelet function is regulated by numerous molecules, and congenital abnormalities of these molecules result in a variety of congenital platelet function disorders. Among these, Glanzmann thrombasthenia (GT), caused by a congenital deficiency or molecular abnormality in GPIIb-IIIa (αIIbβ3), and Bernard-Soulier syndrome (BSS), caused by a congenital deficiency or molecular abnormality in the GPIb-IX-V complex, are representative disorders that manifest as severe bleeding tendency from infancy. GT and BSS are diagnosed mainly by flow cytometry of membrane glycoproteins in addition to conventional light transmission aggregometry. Platelet transfusions are indicated for bleeding refractory to standard hemostatic measures, and recombinant factor VIIa (rFVIIa) has been shown to be effective in GT. rFVIIa has conventionally been used in GT patients refractory to platelet transfusion due to alloantibody production, but is now available in Japan regardless of alloantibody status or platelet transfusion refractoriness. rFVIIa should be considered especially in patients at risk of alloantibody production due to platelet transfusion.
2026-05-01 | Multidisciplinary approaches to coexisting Glanzmann thrombasthenia and juvenile polyposis syndrome.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder from defects in the αIIbβ3 integrin receptor, impairing platelet aggregation and often overlooked due to normal platelet counts. Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder with multiple gastrointestinal polyps and increased colorectal cancer risk. Their co-occurrence is exceedingly rare and challenging. We report a 19-year-old male who was diagnosed with GT at age 5 after rectal bleeding from a gastrointestinal polyp requiring polypectomy and transfusions; platelet aggregation studies confirmed GT. At age 9, genetic testing established JPS. In 2014 he developed recurrent severe bleeding-hematochezia, melena, and hemarthrosis-managed with recombinant activated factor VII (rFVIIa), blood transfusions, and supportive care including vitamin D. Additional findings included duodenal lymphangioma requiring resection, vitamin D deficiency with bone pain and complex regional pain syndrome, and chronic idiopathic hypertension treated with antihypertensives. This case highlights rFVIIa effectiveness and the need for multidisciplinary, long-term follow-up and care.
2026-04-09 | Platelet transfusion refractoriness in Glanzmann thrombasthenia: a case report with literature review.
Glanzmann thrombasthenia (GT) is a rare inherited platelet function disorder characterized by a deficiency or dysfunction of the αIIbβ3 integrin, leading to impaired platelet aggregation. Platelet transfusion refractoriness (PTR) represents a therapeutic challenge, often resulting from alloimmunization against HLA antigens or the αIIbβ3 complex. We report the case of a patient with type I GT, who presented with recurrent mucosal hemorrhages and chronic anemia requiring repeated transfusions. By the age of 8 years, the patient developed transfusion refractoriness, with hemorrhagic episodes unresponsive to platelet transfusions. Immunologic investigations revealed anti-HLA and anti-αIIbβ3 antibodies. At 14 years of age, a severe hemorrhagic episode with rapid hemoglobin decline was successfully managed with recombinant activated factor VII (rFVIIa). Management of PTR in GT represents a major clinical challenge, frequently associated with anti-HLA or anti-αIIbβ3 antibodies. In high-resource settings, transfusion strategies are guided by antibody specificity: HLA-compatible or human platelet antigen-compatible platelets are used for patients with anti-HLA or anti-human platelet antigen antibodies, respectively, while rFVIIa is reserved for individuals with anti-αIIbβ3 antibodies. In LMIC such as Tunisia, prevention of alloimmunization through systematic leukoreduction is essential. When PTR occurs, donor selection by crossmatching, when feasible, and judicious use of rFVIIa for life-threatening hemorrhage remain key therapeutic options.
2026-04-08 | Congenital thrombopathies in southern Tunisia : A multicenter study.
congenital thrombopathies (CTs) are rare bleeding disorders resulting from platelet dysfunction which may also be associated with thrombocytopenia. To date, the prevalence of CT in Tunisia has not been established. The aim of this study was to describe the various types of CT and the associated hemorrhagic manifestations observed in a cohort from southern Tunisia. We retrospectively collected clinical and laboratory data of patients with CT who were followed up over 43 years (1982 - 2024) in the pediatric and hematology departements of a university hospital center in southern Tunisia. The diagnosis of thrombopathy was established based on flow cytometry analysis and/or light transmission aggregometry and/or molecular analysis. We identified 60 patients (35 men and 25 women). The mean age at diagnosis was 61.7 months (1 month-70 years). Consanguinity was noted in 71.6% of cases (n=43). A family history of thrombopathy was reported in 51.6% of cases (n=31). The presenting symptoms at diagnosis were spontaneous or provoked bleeding (n=56) and easy bruising associated with thrombocytopenia within the first 48 hours of life (n=1). The etiologies of the thrombopathies were as follows : Glanzmann thrombasthenia (n=54), Bernard Soulier syndrome (n=5) and Wiskott Aldrich syndrome (n=1). Glanzmann thrombasthenia was the most prevalent thrombopathy in our cohort, likely attributed to the high rate of consanguinity in our region.
antibodies
2026-02-01 | Antiboby mediated Acquired Glanzmann Thrombasthenia – a diagnostic and therapeutic challenge – with Concizumab as Promising Therapeutic Approach: A Case Report
Introduction Acquired Glanzmann thrombasthenia (aGT) is a rare autoimmune bleeding disorder caused by inhibitory antibodies against GPIIb/IIIa, leading to impaired platelet aggregation and severe bleeding. This closely mimics classic GT where isoantibodies render donor platelets ineffective. Thus, rFVIIa and antifibrinolytics are the treatment of choice [ 1 ]. Immunosuppressive approaches such as corticosteroids, intravenous immunoglobulins, and rituximab show variable efficacy, particularly in the presence of IgM antibodies [ 2 ] [ 3 ]. A 12‑year‑old boy, ten years after heart transplantation due to CMV‑induced myocarditis, presented with recurrent severe gastrointestinal bleeding and extensive petechiae. Routine coagulation parameters were normal, except mild thrombocytopenia (around 100,000/µl). After diagnostic gastrointestinal biopsies, he suffered life-threatening hemorrhage requiring massive transfusion of erythrocytes, platelets, fresh frozen plasma, rFVIIa, fibrinogen, and FXIII to stabilize. Method Light transmission aggregometry (LTA) showed absent aggregation responses except ristocetin (1M) consistent with the pattern of GT. MAIPA revealed platelet antibodies against the GPIIb/IIIa complex. LTA with platelets of a healthy control and patient`’s plasma failed to improve aggregation consistent with the hypothesis of antibody-mediated aGT. Further investigations with antibody depletion and purification raised the suspicion that besides IgG antibodies also IgM anti-platelet antibodies play a significant role in this thrombocytopathy. Next‑generation sequencing revealed a heterozygous LRBA deficiency as a potential cause of immune dysregulation. Results Specific treatment included plasma exchange, high‑dose corticosteroids, intravenous immunoglobulins, rituximab, daratumumab, and abatacept, without improvement in platelet function. The patient experienced several life-threatening bleeding events, with only short term bleeding control upon administration of recombinant FVIIa and antifibrinolytics, followed by severe rebleeding with every dose reduction. Due to the need for prophylactic measures to prevent refractory bleedings, Concizumab, a monoclonal antibody inhibiting tissue factor pathway inhibitor (TFPI), was initiated as off‑label therapy after approval for cost coverage. Following subcutaneous administration, bleeding episodes ceased for the first time since disease onset. No further major hemorrhages occurred, petechiae regressed, and transfusion requirements stopped. Conclusion Acquired GT can cause sudden life-threatening bleedings even in children. This case demonstrates that aGT with persistent IgM anti‑GPIIb/IIIa antibodies can be resistant to standard treatments and immunosuppression. Concizumab led to sustained clinical improvement and effective bleeding control , representing a promising therapeutic approach for refractory aGT. TFPI inhibition may offer a novel concept for managing severe autoimmune and congenital platelet function disorders. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-02-01 | Procoagulant Platelets and Thrombin Generation in Glanzmann Thrombasthenia: Insights into Bleeding and the Failing Compensatory Mechanism with Desmopressin on Platelets
Introduction Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet disorder caused by mutations in the ITGA2B or ITGB3 genes, leading to defective integrin αIIbβ3 function and impaired platelet aggregation. GT patients exhibit severe bleeding symptoms, but the relationship between procoagulant platelets, thrombin generation, and bleeding severity remains poorly understood. Studies in hemophilia suggest a compensatory role for procoagulant platelets in mitigating bleeding severity, as highlighted by recent findings [ 1 ]. However, the procoagulant potential of platelets has not been explored in GT patients, where integrin αIIbβ3 dysfunction fundamentally alters platelet behavior. Objective: This study aims to evaluate the procoagulant potential of platelets and their impact on thrombin generation in GT patients, providing insights into compensatory mechanisms in hemostasis. Method A total of 9 samples from 5 Glanzmann patients and 9 healthy controls, were analyzed. Platelets were quantified using flow cytometry, thrombin generation was assessed via calibrated automated thrombography, and bleeding severity was evaluated using the ISTH-BAT (scores: 17–45). The impact of Desmopressin on platelet procoagulant activity was also investigated. Results The procoagulant platelet formation was significantly reduced in GT patients (8.87%, n =9) compared to healthy controls (34.46%, n =24, p =0.0002) after TRAP-6/CVX stimulation. Surprisingly, despite this reduction, GT patients demonstrated significantly increased thrombin generation (area under the curve: 2278 nM·min vs. 1541 nM·min in controls, p =0.0021). The thrombin peak was not significantly different ( p =0.0671; 126.8 nM vs. 96.37 nM); however, the lag time ( p =0.0008; 12.35 vs. 7.286 min) and time to peak ( p =0.0019; 25.45 vs. 17.75 min) were markedly prolonged in GT patients. Notably, the ISTH-BAT scores did not correlate with procoagulant platelet levels, suggesting that bleeding severity is independent of procoagulant potential induced by TRAP-6/CVX. Desmopressin significantly enhanced procoagulant platelet formation in healthy controls ( p =0.0095; 28.73% vs. 12.15%) but showed no effect in GT patients ( p =0.4983; 6.037% vs. 4.904%). Conclusion GT patients exhibit a profound reduction in procoagulant platelet formation but demonstrate compensatory increases in thrombin generation, albeit with delayed kinetics. This compensatory mechanism does not translate into reduced bleeding severity, as evidenced by the lack of correlation with ISTH-BAT scores. The inability of Desmopressin to enhance procoagulant platelet formation in GT further underscores the unique pathophysiology of the disorder. Future studies are needed to explore therapeutic strategies targeting thrombin generation pathways to mitigate bleeding in GT patients. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-03 | Sutacimig, a novel bispecific antibody for prophylactic treatment of glanzmann thrombasthenia: Analysis of a Phase 2 study
Abstract Background: Sutacimig is a bispecific antibody designed to bind and accumulate endogenous factor VIIa (FVIIa) and localize it to activated platelets via TLT-1, thereby enhancing thrombin generation at sites of vascular injury. Glanzmann thrombasthenia (GT) is a severe genetic bleeding disorder characterized by deficient or dysfunctional expression of αIIbβ3 integrin, resulting in impaired platelet aggregation and frequent bleeding episodes. No prophylactic therapy exists, leading to substantial morbidity including iron deficiency anemia, heavy menstrual bleeding, and impaired quality of life. Early results from this study evaluating sutacimig as prophylactic therapy for GT demonstrated encouraging safety and >50% reduction in the median annualized treated bleeding rate (ATBR) (Sivapalaratnam, EAHAD & ISTH, 2025). Here, we present interim results from the fully enrolled Phase 2 study (NCT06211634); complete results will be presented at ASH. Methods: We conducted a multicenter, open-label study evaluating prophylactic subcutaneous sutacimig in adults (18-67 years) with confirmed GT. Following completion of the single ascending dose module the multiple ascending dose (MAD) module opened. Treated bleeding events were prospectively recorded in a 6-week run-in period; subsequently, participants received sutacimig for 12 weeks with option to continue in a long-term extension. The primary endpoint in the MAD was safety, with additional endpoints including pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy based on ATBR reduction. Results: As of data cutoff on May 23, 2025, the MAD was fully enrolled with n=34 participants; median age 40.5 years, 47% female. Participants were enrolled into four dosing regimens: 0.3 mg/kg Q2W (n=11); 0.6 mg/kg Q2W (n=13); 0.9 mg/kg Q2W (n=5); 0.3 mg/kg Q1W (n=5). Median exposure in the MAD plus long-term extension was 3.2 months (range 1.7-11.3). AEs were reported in 82% of participants with the majority of AEs graded as mild to moderate. The most common reported AEs (≥10%) were headache (18%), nasopharyngitis (18%), D-dimer elevation (18%), dizziness (12%), and fatigue (12%). Neutralizing anti-drug antibodies developed in 4/34 participants; 2/4 resolved with continued dosing without clinical sequelae. A DVT (Grade 2) was observed in one participant in the 0.9 mg/kg Q2W cohort who discontinued due to this AE. Dosing in this cohort was subsequently suspended. The event is resolving with outpatient treatment. PK and PD (FVIIa) demonstrated a dose-proportional increase with FVIIa accumulation of ~2-4 fold above baseline at ongoing dose levels (0.3-0.6 mg/kg). Interim efficacy analyses demonstrated sutacimig achieved >50% reduction in median ATBR compared to run-in period. Conclusions: In this interim analysis, sutacimig was well tolerated at ongoing dose levels (0.3-0.6 mg/kg) with evidence of clinical activity, with a >50% reduction in median ATBR with sutacimig prophylaxis. Updated safety and efficacy analyses will be conducted following completion of 12-week follow-up for all participants. These data are expected to inform dose selection and support planning for a Phase 3 trial evaluating prophylactic sutacimig for GT.
2025-04-16 | Advanced diagnostics and novel therapeutics for platelet function disorders
Platelet function plays a critical role in hemostasis, and dysfunction in this mechanism is implicated in a range of bleeding disorders. The most rare inherited platelet function disorders (IPFDs) are relatively easy to diagnose. However, the more prevalent IPFDs often show a high diagnostic difficulty, leading to underdiagnosis. In terms of treatment of IPFD patients, no prophylactic treatment is available, causing high patient burden and relatively low quality of life for patients suffering from a severe IPFD. This thesis describes novel diagnostic and therapeutic approaches for this group of disorders. Advanced diagnostics … In Chapter 2, we described the characterization of a tetrameric nanobody-based glycoprotein VI (GPVI) platelet agonist and compared it to current agonists used in platelet diagnostics, that are hard to standardize and difficult to produce. We showed that our nanobody is able to discriminate between healthy controls and GPVI-related platelet disorders to a similar extent as collagen or cross-linked collagen-related peptide (CRP-XL). In this way, we provide a more stable, easier to produce alternative to current GPVI agonists, which is beneficial for standardization of platelet diagnostics. In Chapter 3, we have validated a novel whole blood-based rapid test for delta storage pool disease (δ-SPD), based on platelet ATP secretion. The current standard for diagnosis of δ-SPD is laborious, has a long turn-around time and requires large volumes of blood. We aimed to introduce a microarray that decreases the labor intensiveness, turn-around time and required volume of blood. With its high sensitivity, this test is able to exclude δ-SPD, decreasing the need to send all patients for more advanced diagnostic techniques. In Chapter 4, we have compared the platelet proteome of healthy controls and people with Glanzmann thrombasthenia (GT). We have shown that platelets from GT patients show downregulation of several platelet specific α-granule proteins. … and novel therapeutics for inherited platelet function disorders In Chapter 5, we introduced a potential novel prophylactic treatment for inherited bleeding disorders. HMB-001 is a bispecific antibody that recognizes (activated) coagulation factor VII (FVII(a)) and TREM-like transcript-1 (TLT-1) on the activated platelet surface, thereby targeting FVIIa to the platelet surface and boosting fibrin formation to compensate for defects in primary hemostasis. Our preclinical data has shown that HMB-001 is effective in enhancing fibrin formation ex vivo, prolonging endogenous FVIIa half-life in nonhuman primates and potentiating FVIIa hemostatic activity in mouse bleeding studies. HMB-001 has therefore potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
2024-08-22 | Targeting tissue factor pathway inhibitor with concizumab to improve hemostasis in patients with Glanzmann thrombasthenia: an in vitro study.
Glanzmann thrombasthenia (GT) is caused by an inherited defect of platelet αIIbβ3 integrin. Concizumab, a monoclonal antibody specific for tissue factor pathway inhibitor, abolishes its anticoagulant effect. To evaluate the in vitro ability of concizumab to improve hemostasis in GT. The effects of concizumab were evaluated in whole blood or platelet-rich plasma from GT patients (n = 5-9) using a thrombin generation assay, rotational thromboelastometry (ROTEM), a global fibrinolytic capacity assay, and a flow chamber assay (Total Thrombus formation Analysis System). Washed platelets (WPs) and 20 nM recombinant activated factor VII (rFVIIa) were included for comparison. The lag time in the thrombin generation assay was significantly longer (+85%; P < .0001) in GT patients than in controls. WPs, rFVIIa, and concizumab each significantly improved thrombin generation profiles. The ROTEM clotting time (CT) was significantly longer in GT patients than in controls (677 seconds vs 523 seconds; P = .03). However, CT improved after adding WPs, rFVIIa, or concizumab. Under flow, occlusive thrombi were present in all healthy controls after 10 minutes, whereas platelet-fibrin depositions were not seen in GT patients. Subocclusive or occlusive thrombi formed when GT blood was mixed with WPs, rFVIIa, or concizumab. Clots in GT platelet-rich plasma were more susceptible to fibrinolysis and were improved by WPs, rFVIIa, or concizumab. Concizumab enhanced thrombin generation, decreased the ROTEM CT, improved thrombus formation under flow, and reduced clot lysis. Our results demonstrate the potential of concizumab for subcutaneous prophylaxis in GT patients.
other
2026-05-29 | Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.
Glanzmann Thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. While GT patients typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 GT patients, eight consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized megakaryocyte cell lines (imMKCLs), focusing on two modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3D silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production, independent of the type of variant. While TRAP-activated in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 prior to activation mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3 deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, while re-expression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.
2025-11-27 | Molecular Pathogenesis of Inherited Platelet Dysfunction.
Inherited platelet function disorders (IPFD) are characterized by normal platelet count and morphology but impaired function due to pathogenic variants in genes encoding membrane receptors, granule constituents, or intracellular signaling proteins. Glanzmann's thrombasthenia, the most representative IPFD, results from ITGA2B or ITGB3 mutations that disrupt the αIIbβ3 integrin complex, producing severe mucocutaneous bleeding. Advances in molecular genetics have expanded the IPFDs landscape to include defects in other platelet receptors (Glycoprotein (GP)-VI, P2Y12, and thromboxane A2[TxA2]-R), signaling mediators (RASGRP2, FERMT3, G-protein regulators, PLC, and TxA2 pathway enzymes), and granule biogenesis disorders such as Hermansky-Pudlak and Chediak-Higashi syndromes. High-throughput sequencing technologies, including long-read approaches, have greatly improved diagnostic yield and clarified genotype-phenotype correlations. Clinically, bleeding severity varies from mild to life-threatening, and management relies on antifibrinolytics, desmopressin, or platelet transfusion; recombinant activated factor VII and hematopoietic stem cell transplantation are reserved for selected cases. Emerging strategies such as gene therapy and bispecific antibodies that link platelets and coagulation factors represent promising advances toward targeted and preventive treatment. A better knowledge of the clinical features and understanding molecular pathogenesis of IPFDs not only enhances diagnostic precision and therapeutic options but also provides key insights into platelet biology, intracellular signaling, and the broader mechanisms of human hemostasis.
2020-07-14 | Integrin β3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion.
Integrin β3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether β3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with β3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an αIIb deficiency or healthy subjects. The β3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that β3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine)720-722 motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/β3/LPL complex that is required for β3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in β3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH720-722-mutated β3 genes. This study reveals a hypertriglyceridemia in both β3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of β3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with β3-deficient Glanzmann thrombasthenia.
2016-01-20 | Megakaryocyte- and megakaryocyte precursor–related gene therapies
Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual's lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.
2015-07-01 | Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options
Abstract: Glanzmann’s thrombasthenia (GT) is a genetic platelet surface receptor disorder of GPIIb/IIIa (ITG αIIbß3), either qualitative or quantitative, which results in faulty platelet aggregation and diminished clot retraction. Spontaneous mucocutaneous bleeding is common and can lead to fatal bleeding episodes. Control and prevention of bleeding among patients with GT is imperative, and remains challenging. Local measures, including anti-fibrinolytic therapy, with or without platelet transfusions, used to be the mainstay of therapy. However, in recent years the use of recombinant factor VIIa (rFVIIa) has increased significantly, with excellent response rates in treating and preventing hemorrhage among GT patients. Gene therapy and stem cell transplantation offer a potential cure of this disease, but both are costly and remain experimental at this point. This manuscript offers a comprehensive review of our understanding of GT and the available treatment options. Keywords: Glanzmann, thrombasthenia, treatment
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Drug Discovery Landscape
5 orphan drug designations for Glanzmann thrombasthenia, including 1 approved therapy.
5 orphan drug designations for Glanzmann thrombasthenia, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
megatemlocel | cell therapies | FDA | HemaCell Biotechnology Inc. | |
Sutacimig | antibodies | EMA | Hemab ApS | |
human IgG4 bispecific antibody recognizing factor VIIa and TLT-1 | antibodies | FDA | Hemab ApS | |
coagulation factor VIIa (recombinant) [NovoSeven RT] | proteins | FDA | Approved | Novo Nordisk Inc. |
Coagulation factor VIIa (recombinant) | proteins | FDA | Novo Nordisk, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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